Summary 1) Based on analysis of Medicare (CMS) national claims data, we have determined that the epidemiology of mycobacterial disease in the United States has changed over the last 20 years, with a decline in pulmonary tuberculosis and an increase identified in pulmonary nontuberculosis mycobacterial disease. The prevalence of PNTM is increasing significantly across all regions of the United States and among both men and women. Significant racial/ethnic and geographic differences in PNTM prevalence suggest important gene-environment interactions. From 1997-2007, the annual prevalence significantly increased from 20 (95% CI: 18-23) to 47 (95% CI: 44-51) cases/100,000 persons, or 8.2% per year. The period prevalence was 112 (95% CI: 108-116) cases/100,000 persons, although prevalence was two-fold higher among Asians/Pacific Islanders than among whites (228 vs. 116 cases/100,000 persons). One-third of PNTM cases resided in southeastern states, which had a period prevalence of 131 (95% CI: 122-140) cases/100,000 persons; however, western states had the highest period prevalence at 149 (95% CI: 136-163) cases/100,000 persons, with Hawaii having the highest prevalence at 396 (95% CI: 170-211) cases/100,000 persons. PNTM cases had more comorbid conditions than non-cases and were 40% more likely to die than non-cases (OR=1.4 95% CI: 1.3-1.6). Overall, women were 1.4 (95% CI: 1.3-1.5) times more likely to be a PNTM case than men. Relative to whites, Asians/Pacific Islanders were twice as likely to be a case (OR=2.0 95% CI: 1.2-2.5) while blacks were half as likely (OR=0.5 95% CI: 0.4-0.6). Based on geographic differences in NTM prevalence identified, we became interested in further understanding the geographic variability of NTM lung disease and possible gene-environment interactions. The ubiquitous prevalence of the NTM organisms and the rarity of NTM disease support the role for a genetic susceptibility to disease from these organisms. We have conducted further analysis of these claims data and have identified geographic clusters of disease by country in the US associated with specific environmental factors such as the degree of surface area comprised of water and the climatic factors related to conversion of surface water to atomspheric water vapor. 2) Bronchiectasis is a condition characterized by permanent bronchial dilation and repeated infections, particularly with mycobacteria. The Laboratory of Clinical Infectious Diseases, NIAID, is currently conducting clinical studies of bronchiectasis natural history. We sought to describe the trend, associated conditions and risk factors for bronchiectasis among adults 65 years. Bronchiectasis prevalence increased significantly from 2000-2007 in the Medicare outpatient setting and varied by age, sex and race/ethnicity. A 5% sample of the Medicare outpatient claims database was analyzed for bronchiectasis trends among beneficiaries aged 65 years from 2000-2007. Bronchiectasis was identified using the ICD-9-CM claim diagnosis codes for acquired bronchiectasis. Period prevalence was used to describe sex and race/ethnicity specific rates and annual prevalence was used to describe trends and age specific rates. We estimated trends using Poisson regression and odds of bronchiectasis using multivariate logistic regression. From 2000-2007, 22,296 persons had at least one claim for bronchiectasis. The eight year period prevalence of bronchiectasis was 1106 cases/100,000 persons. Bronchiectasis increased by 8.7% per year. We identified an interaction between number of thoracic CT scans and race/ethnicity; there was a significantly greater increase in bronchiectasis period prevalence by number of thoracic CT scans among Asians as compared to whites or blacks. Among persons with one CT scan, Asians had a 2.5 and 3.9 fold higher period prevalence as compared to whites and blacks. This increase could be due to a true increase in the condition or increased recognition of previously undiagnosed cases. 3) PNTM risk factors for mortality: Although the disease burden of pulmonary nontuberculous mycobacteria (NTM) is increasing, data are lacking on risk factors for mortality. Predictors of all-cause mortality with pulmonary NTM include low BMI, low pulmonary function, and high levels of inflammation. To estimate the mortality rate among persons with pulmonary NTM and to describe predictors of mortality, we conducted a retrospective review of patient data from the NIH pulmonary NTM natural history cohort. Kaplan-Meier survival curves and Cox Proportional Hazard Models were used to describe survival. The study population for analysis comprised 106 patients, including 26 (25%) who progressed to death and 80 surviving. The mean age at death was 67 years, and the median length of follow-up was 4.9 years. The mortality rate was 4.02 per 100 person-years. Sex, racial/ethnic group, age at entry, and follow-up time were similar between deceased and surviving patients. Pulmonary hypertension and chronic obstructive pulmonary disease (COPD) were more prominent in deceased patients. No significant differences were observed in baseline organism. Mean baseline Body Mass Index (BMI) was 20.0 for deceased patients and 22.2 for surviving patients (p<0.05), with a decrease in BMI observed after one year in patients who died. Deceased patients had significantly lower pulmonary function and higher levels of inflammation at entry (p<0.0005).